Ruthenium-Catalyzed Cyclization of Aromatic Nitriles with Alkenes

Letter pubs.acs.org/OrgLett

Ruthenium-Catalyzed Cyclization of Aromatic Nitriles with Alkenes: Stereoselective Synthesis of (Z)‑3-Methyleneisoindolin-1-ones Mallu Chenna Reddy and Masilamani Jeganmohan* Department of Chemistry, Indian Institute of Science Education and Research, Pune 411021, India S Supporting Information *

ABSTRACT: Aromatic nitriles underwent cyclization with activated alkenes in the presence of a ruthenium catalyst, AgSbF6, and Cu(OAc)2·H2O providing substituted 3-methyleneisoindolin1-ones with high Z-stereoselectivity. The Z-stereoselectivity of the 3-methyleneisoindolin-1-one moiety was controlled by the intramolecular hydrogen bonding.

I

By using the traditional methods and metal-catalyzed reactions,3−7 isoindolinone and (E)-3-methyleneisoindolin-1one derivatives are efficiently prepared, but, Z-stereoselective 3-methyleneisoindolin-1-one synthesis is not well demonstrated because of the rapid Z to E stereoselective isomerization.8 Herein, we report a ruthenium-catalyzed annulation of aromatic nitriles9 with activated alkenes to yield Z-stereoselective 3-methyleneisoindolin-1-ones in good yields in a highly regioselective manner. In the reaction, Z-stereoselectivity was controlled by the intramolecular hydrogen-bonding. Treatment of 3,4-dimethoxybenzonitrile (1a) with methyl acrylate (2a) in the presence of [[RuCl2(p-cymene)]2] (5.0 mol %), AgSbF6 (20 mol %), and Cu(OAc)2·H2O (2.0 equiv) in acetic acid (AcOH) at 120 °C for 36 h gave 3-methyleneisoindolin-1-one 3aa in 75% isolated yield in a high Z-stereoselectivity (eq 1)

soindolinone is a core structure unit present in various natural products and biologically active molecules.1 In particular, the 3-methyleneisoindolin-1-one structural motif is found in several biologically active natural products and designed pharmaceutical molecules.2 Traditionally, 3-methyleneisoindolin-1-ones are prepared by the reaction of phthalimides with Wittig reagents and nucleophilic addition of organometallic reagents into phthalimides followed by dehydration.3 Alternatively, it can also be prepared by metal-catalyzed intramolecular cyclization of o-alkynylbenzamides, coupling of 2-halobenzamides with terminal alkynes, and intermolecular coupling of substituted ynamides or o-vinylbenzamides with aromatic boronic acids.4 However, the control of regio- and stereoselectivity and the observation of competitive side products are critical problems in these reactions. In addition, preactivated halo-substituted aromatics are required to prepare the key starting materials. Recently, isoindolinone derivatives have been efficiently prepared by metal-catalyzed oxidative cyclization of aromatic amides with alkenes without having any preactivated species on the aromatic moiety via chelation-assisted C−H bond activation.5,6 N-Aryl- or -tosylbenzamides reacted with alkenes in the presence of palladium or rhodium catalysts yielding five-membered isoindolinones.6a−c N-Alkoxybenzamides reacted with activated alkenes in the presence of palladium catalyst yielding (E)-3methyleneisoindolin-1-one derivatives.6d,e In the meantime, Nmethylsubstituted benzamide or primary benzamides reacted with n-butyl acrylate to afford 3-methyleneisoindolin-1-ones.6f However, the corresponding reaction was studied with only two primary benzamides and a single 3-methoxy-N-methylbenzamide, and the observed yield was also very low. In fact, N-alkylsubstituted benzamides and primary benzamide are not suitable substrates for the cyclization with alkenes because of their sluggish reactivity. However, pyridine-substituted amides underwent cyclization with alkenes efficiently in the presence of rhodium catalyst affording cis and trans stereoisomeric mixtures of 3-methyleneisoindolin-1-ones.6g−i Apart from the benzamides, aromatic ketoximes reacted with isocyanates to give a mixture of cis and trans stereoisomeric 3-methyleneisoindolin-1ones.7 © XXXX American Chemical Society

(for detailed optimization studies, see the Supporting Information). The Z-stereoselectivity of compound 3aa was controlled by the intramolecular hydrogen bonding of the N−H group of 3aa to the carbonyl group of the ester moiety of 3aa. The catalytic reaction is also highly regioselective; the ortho C−H bond activation takes place selectively at a less hindered side of aromatic 1a. It is important to note that until now methyleneisoindolin-1-ones have been prepared from substituted benzamides or aromatic ketoximes with alkenes. Here, we show the synthesis of methyleneisoindolin1-ones from easily available aromatic nitriles. The scope of the cyclization reaction was examined with various alkenes (Table 1). Ethyl acrylate (2b), n-butyl acrylate (2c), and cyclohexyl acrylate (2d) underwent cyclization with 1a, yielding cyclization products 3ab−ad in 67%, 70%, and 74% yields, respectively (entries 1−3). Interestingly, 2,2,2-trifluoroethyl Received: August 11, 2014

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Table 1. Scope of the Activated Alkenes 2b−ga

Table 2. Cyclization of Nitriles 1 with Alkenes 2c or 2ga

a

All reactions were carried out using 1a, alkenes 2b,c (4.0 equiv), 2d−f (3.0 equiv), and 2g (1.2 equiv), [{RuCl2(p-cymene)}2] (5 mol %), AgSbF6 (20 mol %), and Cu(OAc)2.H2O (2.0 equiv) in AcOH (3.0 mL) at 120 °C for 36 h. bIsolated yield.

acrylate (2e) and 2-hydroxyethyl acrylate (2f) also efficiently reacted with 1a giving cyclization products 3ae and 3af in 62% and 61% yields, respectively (entries 4 and 5). In the product 3af, a free hydroxy group was converted into acetate group in the presence of AcOH. Surprisingly, vinyl sulfone (2g) also reacted efficiently with 1a, providing cyclic compound 3ag in 65% yield, respectively (entry 6). Next, the reaction was tested with other alkenes such as methyl vinyl ketone, acrylonitrile, and styrenes. However, in the reaction, no cyclization product was observed. It seems a good coordinating group such as ester and SO2Phsubstituted alkenes were suitable for the reaction. The present catalytic reaction was also successfully extended with various substituted aromatic nitriles (Table 2). Thus, electron-rich aromatic nitriles such as 4-hydroxy- (1b), 4-methoxy- (1c), and 4-methylbenzonitriles (1d) and benzonitrile (1e) efficiently reacted with phenyl vinyl sulfone (2g) to give isoindolinone derivatives 3bg−eg in good to moderate yields in a highly Z-stereoselective manner (entries 1−4). The structure of compound 3cg was supported by a single-crystal X-ray diffraction (see the Supporting Information). Halogen groups such as 4-iodo- (1f), 4-bromo- (1g), 4-chloro- (1h) and 4-fluorobenzonitriles (1i) were nicely involved in the reaction, providing cyclization products 3fg−ig in good yields in a highly stereoselective manner (entries 5−8). Very interestingly, electron-deficient aromatic nitriles such as 4-nitrobenzonitriles (1j), 4-methyl ester benzonitriles (1k), and 4-formylbenzonitriles (1l) nicely reacted with phenyl vinyl sulfone (2g) affording products 3jg−lg in 61%, 56%, and 52% yield, respectively, in a highly regio- and stereoselective manner (entries 9−11). It is important to note that a free OH and sensitive I, Br, ester, CHO, and NO2 groups were not affected. Further, 4-(dimethylamino)benzonitrile (1m), sterically hindered o-methoxybenzonitrile (1n), and 1-naphthonitrile (1o) reacted with n-butyl acrylate (2c) providing cyclization products 3mc−oc in 59%, 51%, and 56% yields, respectively (entries 12−14). Next, the cyclization reaction was tested with unsymmetrical aromatic nitriles such as m-bromobenzonitrile (1p), 2-naphthonitrile (1q), and 3,4-dimethylbenzonitrile (1r) with 2c or 2g (Scheme 1). In these substrates, two different regioselective products are possible. However, the reaction is highly regioselective, and the ortho C−H activation takes place at the less hindered

a

All reactions were carried out using 1a−o, alkene 2g (1.20 equiv) or 2c (4.0 equiv), [{RuCl2(p-cymene)}2] (5 mol %), AgSbF6 (20 mol %) and Cu(OAc)2·H2O (2.0 equiv) in acetic acid (3.0 mL) at 120 °C for 36 h. bIsolated yield. cReaction was carried out for 42 h. dReaction was carried out for 39 h. eReaction was carried out for 45 h.

Scheme 1. Regioselective Studies

side, giving products 3pg−3rg in 45%, 59%, and 59% yields, respectively (Scheme 1), whereas in the substrate 1s, the ortho C− H bond activation takes place at the sterically hindered side, providing cyclization product 3sg in 77% yield (Scheme 1). Isoindolin-1-one derivatives are widely used as a fluorescent marker for labeling biomolecules.2 To learn the optical behavior, we have performed the following reaction and monitored the absorbance and fluorescence of the product (eq 2). Treatment of pyrene-1-carbonitrile (1t) with 2g provided cyclization product B

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reaction conditions, providing N-arylated product 7b in 95% yield. Then, the ester group of compound 7b was converted into COOH derivative 8 in 89% yield in the presence of 15% aqueous K2CO3 (2.0 mL) in MeOH at 80 °C for 4 h. It is known that the compound 8 can be easily converted into the pharmaceutical molecule 9 and 10.7 A possible reaction mechanism is proposed in Scheme 3 to account for the present cyclization reaction.5−9 Three different 3tg in 32% yield. Compound 3tg shows absorbance at 415 nm and fluorescence at 470 nm (see the Supporting Information). The starting material pyrene-1-carbonitrile (1t) shows absorbance at 355 nm, and fluorescence shows three characteristic bands at 383, 402, and 425 nm. After installation of the isoindolin-1-one moiety, the fluorescence was enhanced 55 nm and a broad single emission band with red shift was observed. Next, the free N−H group of 3aa was attempted to protect with di-tert-butyl dicarbonate (4) (2.0 equiv) in the presence 4-(dimethylamino)pyridine (4-DMAP) (2.0 equiv) in CH3CN at room temperature for 1 h (eq 3). In the reaction, N-BOC-protected

Scheme 3. Proposed Mechanism

catalytic reactions were involved in the reaction. In the first step, Cu(OAc)2 likely acts as a Lewis acid to which the nitrile group of benzonitrile 1 is coordinated to provide intermediate 11. In this stage, the Lewis acid likely reduces the electron density of the nitrile group followed by hydration, providing benzamide 12, and regenerates the active Cu(OAc)2.11a In the second catalytic cycle, AgSbF6 likely removes the chloride ligand from [[RuCl2(p-cymene)]2] complex followed by the ligand exchange with Cu(OAc)2 giving a cationic ruthenium species 13. Coordination of the amide group of 12 into the ruthenium cationic species 13 followed by the ortho-metalation provides a five membered ruthenacycle 14 and AcOH.11b,c Coordinative insertion of alkene 2 into the Ru−carbon bond of ruthenacycle 14 affords ruthenacycle intermediate 15. β-Hydride elimination of intermediate 15 in the presence of Cu(OAc)2 provides alkenylated product 16 and regenerates the active ruthenium species 13. In the third catalytic cycle, the amide group of product 16 coordinates with ruthenium species 13 followed by the intramolecular coordination of double bond to afford intermediate 17 and AcOH. Intramolecular coordinative insertion of N−Ru bond of intermediate 17 into the alkene moiety via aza-Michael addition provides intermediate 18a. Subsequent β-hydride elimination of intermediate 18a in the presence of Cu(OAc)2 provides product 3 and regenerates ruthenium species 16. In fact, in the intramolecular insertion of N−Ru bond of intermediate 17 into the double bond of alkene moiety, two different diastereoselective intermediates such as the ester moiety of alkene and cyclic tertiary C−N−H bond are syn to each other (18a) and anti to each other (18b) via aza-Michael addition (Scheme 3, eq 5). These intermediates only decide the nature of

compound 5 was observed in 97% yield. It is very interesting to note that in the product 5 alkene Z-stereoselectivity was retained (NOE experiments, see the Supporting Information). Similarly, the N−H group of 3ab was tried by arylating with iodobenzene (6a) in the presence of CuI (20 mol %) and K2CO3 (3.0 equiv) in DMF at 150 °C for 16 h (eq 4). In the reaction, N-arylated product 7a was observed in 71% yield, in which alkene Z-stereoselectivity was also retained. The N-arylation reaction prompted us to explore the possibility of preparation of pharmaceutical molecules 9 and 10 (Scheme 2).7,10 These molecules show sedative activity.10 Scheme 2. Synthesis of Sedative Active Molecules

Treatment of 3,4-dimethylbenzonitrile (1r) with N-butylacrylate (2c) under the optimized reaction conditions provided cyclic compound 3rc in 55% yield in a highly regio- and stereoselective manner (Scheme 2). Later, the free N−H group of compound 3rc was arylated with 4-fluorophenyl iodide (6b) under similar C

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529. (c) Botero Cid, H. M.; Tränkle, C.; Baumann, K.; Pick, R.; MiesKlomfass, E.; Kostenis, E.; Mohr, K.; Holzgrabe, U. J. Med. Chem. 2000, 43, 2155. (d) Omura, S.; Iwai, Y.; Hirano, A.; Nakagawa, A.; Awaya, J.; Tsuchiya, H.; Takahashi, Y.; Masuma, R. J. Antibiot. 1977, 30, 275. (e) Zhuang, Z. P.; Kung, M. P.; Mu, M.; Kung, H. F. J. Med. Chem. 1998, 41, 157. (f) Norman, M. H.; Minick, D. J.; Rigdon, G. C. J. Med. Chem. 1996, 39, 149. (g) De Clercq, E. J. Med. Chem. 1995, 38, 2491. (3) (a) Flitsch, W.; Peters, H. Tetrahedron Lett. 1969, 10, 1161. (b) Pigeon, P.; Decroix, B. Tetrahedron Lett. 1996, 37, 7707. (c) Griesbeck, A. G.; Warzecha, K.-D.; Neudorfl, J.-M.; Gorner, H. Synlett 2004, 13, 2347. (d) Bousquet, T.; Fleury, J.-F.; Daıch, A.; Netchitaılo, P. Tetrahedron 2006, 62, 706. (4) (a) Kundu, N. G.; Khan, M. W. Tetrahedron 2000, 56, 4777. (b) Yao, T.; Larock, R. C. J. Org. Chem. 2005, 70, 1432. (c) Cao, H.; McNamee, L.; Alper, H. Org. Lett. 2008, 10, 5281. (d) Wu, M.-J.; Chang, L.-J.; Wei, L.-M.; Lin, C.-F. Tetrahedron 1999, 55, 13193. (e) Couty, S.; Liegault, B.; Meyer, C.; Cossy, J. Org. Lett. 2004, 6, 2511. (f) Li, L.; Wang, M.; Zhang, X.; Jiang, Y.; Ma, D. Org. Lett. 2009, 11, 1309. (g) Sun, C.; Xu, B. J. Org. Chem. 2008, 73, 7361. (5) Reviews: (a) Thansandote, P.; Lautens, M. Chem.Eur. J. 2009, 15, 5874. (b) Satoh, T.; Miura, M. Chem.Eur. J. 2010, 16, 11212. (c) Colby, D. A.; Bermann, R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624. (d) Song, G.; Wang, F.; Li, X. Chem. Soc. Rev. 2012, 41, 3651. (e) Patureau, F. W.; Besset, T.; Frohlich, R.; Glorius, F. C. R. Chim. 2012, 15, 1081. (f) Zhu, C.; Wang, R.; Flack, J. R. Chem.Asian. J. 2012, 7, 1502. (g) Arokiam, P. B.; Bruneau, C.; Dixneuf, P. H. Chem. Rev. 2012, 112, 5879. (h) Ackermann, L. Acc. Chem. Res. 2014, 47, 281. (i) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147. (j) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788. (k) Bras, J. L.; Muzart, J. Chem. Rev. 2011, 111, 1170. (6) (a) Zhu, C.; Falck, J. R. Org. Lett. 2011, 13, 1214. (b) Wang, F.; Song, G.; Li, X. Org. Lett. 2010, 12, 5430. (c) Zhu, C.; Flack, J. R. Chem. Commun. 2012, 48, 1674. (d) Wrigglesworth, J. W.; Cox, B.; LloydJones, G. C.; Booker-Milburn, K. I. Org. Lett. 2011, 13, 5326. (e) Li, D.D.; Yuan, T.−T.; Wang, G.-W. Chem. Commun. 2011, 47, 12789. (f) Patureau, F. W.; Besset, T.; Glorius, F. Angew. Chem., Int. Ed. 2011, 50, 1064. (g) Wei, X.; Wang, F.; Song, G.; Dub, Z.; Li, X. Org. Biomol. Chem. 2012, 10, 5521. (h) Martınez, A. M.; Rodrıguez, N.; Arrayas, R. G.; Carretero. Chem. Commun. 2014, 50, 6105. (i) Shangjun, C.; Chao, C.; Peng, S.; Chanjuan, X. Org. Lett. 2014, 16, 3142. (j) Ackermann, L.; Pospech, J. Org. Lett. 2011, 13, 4153. (7) Zhou, B.; Hou, W.; Yang, Y.; Li, Y. Chem.Eur. J. 2013, 19, 4701 and references cited therein. (8) Z-Stereoselective synthesis: (a) Lu, Y.; Wang, D.-H.; Engle, K. M.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 5916. (b) Li, J.; John, M.; Ackermann, L. Chem.Eur. J. 2014, 20, 5403. (9) Nitrile-directed reactions: alkoxylation and arylation: (a) Li, W.; Sun, P. J. Org. Chem. 2012, 77, 8362. (b) Li, W.; Xu, Z.; Sun, P.; Jiang, X.; Fang, M. Org. Lett. 2011, 13, 1286. Cyclization: (c) Reddy, M. C.; Manikandan, R.; Jeganmohan, M. Chem. Commun. 2013, 49, 6060. Ru amide cyclization: (d) Ackermann, L.; Lygin, A. V.; Hofmann, N. Angew. Chem., Int. Ed. 2011, 50, 6379. (e) Ackermann, L.; Wang, L.; Wolfram, R.; Lygin, A. V. Org. Lett. 2012, 14, 728. (f) Ma, W.; Ackermann, L. Chem.Eur. J. 2013, 19, 13925 and references cited therein. (g) Parthasarathy, K.; Senthilkumar, N.; Jayakumar, J.; Cheng, C.-H. Org. Lett. 2012, 14, 3478. (h) Arockiam, P. B.; Fischmeister, C.; Bruneau, C.; Dixneuf, P. H. Green Chem. 2011, 13, 3075. (i) Singh, K. S.; Dixneuf, P. H. Organometallics 2012, 31, 7320. (10) Kanamitsu, N.; Osaki, T.; Itsuji, Y.; Yoshimura, M.; Tsujimoto, H.; Soga, M. Chem. Pharm. Bull. 2007, 55, 1682. (11) (a) Kukushkin, V. Yu.; Pombeiro, A. J. L. Inorg. Chim. Acta 2005, 358, 1. (b) Flegeau, E. F.; Bruneau, C.; Dixneuf, P. H.; Jutand, A. J. Am. Chem. Soc. 2011, 133, 10161. (c) Ackermann, L.; Vicente, R.; Potukuchi, H. K.; Pirovano, V. Org. Lett. 2010, 12, 5032.

product. If ester and C−N−H are syn to each other as intermediate 18a, only Z-stereoselective product 3 would be formed. If both are anti to each other as intermediate 18b, E-stereoselective product 3′ would be expected. In the cyclization of aromatic nitrile 1 with 2, intermediate 18a was only formed (eq 5). This is mainly due to the intramolecular hydrogen bonding of C−N−H bond to C−O bond of intermediate 18a. To support the proposed mechanism, aromatic nitrile 3a was treated with Cu(OAc)2·H2O (15 mol %) in acetic acid at 120 °C for 12 h, giving the corresponding benzamide 12a in 85% yield (eq 6). Later, benzamide 12a was treated with n-butyl acrylate

(2c) under similar reaction conditions, providing product 3ac in 68% yield (eq 7). Further, ortho-alkenylated benzamide 16a was prepared separately and treated with [[RuCl2(p-cymene)]2] (5.0 mol %), AgSbF6 (20 mol %), and Cu(OAc)2·H2O (1.5 equiv) in acetic acid at 120 °C for 24 h. In the reaction, product 3ac was observed in 72% yield (eq 7). However, the corresponding conversion did not proceed in the absence of ruthenium catalyst with or without the Lewis acid. In conclusion, we have demonstrated a highly regio- and stereoselective synthesis of (Z)-3-methyleneisoindolin-1-ones in good to moderate yields by a ruthenium-catalyzed annulation of aromatic nitriles with activated alkenes. In the reaction, Z-stereoselectivity was controlled by the intramolecular hydrogen bonding.

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ASSOCIATED CONTENT

S Supporting Information *

General experimental procedure, starting materials preparation, CIF, and characterization details. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the DST (SR/S1/OC-26/2011), India, for support of this research. M.C.R. thanks the CSIR for a fellowship. REFERENCES

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